In hormone replacement therapy (HRT), sometimes also referred to as estrogen replacement therapy, estrogens are administered to prevent or treat symptoms resulting from estrogen deficiency or hypoestrogenism. Hypoestrogenism can occur in both females and males, and can lead to disorders and ailments such as osteoporosis (loss of bone mass), arteriosclerosis, climacteric symptoms such as hot flushes (flashes), sweats, urogenital atrophy, mood disturbances, insomnia, palpitations. Estrogen deficiency has also been associated with cognitive disturbances and Alzheimer's disease.
Hypoestrogenism, and in particular chronic hypoestrogenism, is frequently observed in (peri-)menopausal and post-menopausal women. However, it can also result from hypogonadism or castration, as well as from primary ovarian failure, treatment of e.g. breast cancer with aromatase inhibitor and gonadotropin-releasing hormone analogue treatment of benign gynaecological diseases such as endometriosis, adenomyosis, uterine fibroids (leiomyomas), dysmenorrhoea, menorrhagia and metrorrhagia.
Endogenous and exogenous estrogens fulfil important central nervous and metabolic functions in the female organism: normal estrogen levels make a decisive contribution to a woman's well-being. Notwithstanding the widespread use of estrogens in HRT methods, there are still some unsolved problems. Well-known estrogens, in particular biogenic estrogens (i.e. estrogens that occur naturally in the human body), are eliminated from the blood stream very quickly. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
The most important synthetically altered estrogenic steroid is 17α-ethinyl estradiol (EE). This estrogen is dominant in oral hormonal contraception. Apart from EE, mestranol has been used in a few cases; mestranol is a “prodrug” that is metabolised to EE in the organism. The liver is a target organ for estrogens. The secretion activity that is affected by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. The strong hepatic estrogenicity of ethinyl estradiol and diethylstilbestrol (DES), especially their effect on haemostasis factors, may explain why these synthetic estrogens have been associated with the enhanced risk of thromboembolism. Other undesirable'side-effects that have been reported in relation to the use of synthetic estrogens include fluid retention, nausea, bloating, cholelithiasis, headache, breast pain and an enhanced risk of breast cancer with longer term usage. The aforementioned deficits are of considerable clinical significance when commonly known biogenic or synthetic estrogens are applied. Consequently, there is an as yet unmet need for estrogens that do not display these deficits and which can suitably be employed in HRT methods to effectively replace endogenous ovarian secretion of estradiol, i.e. to treat or prevent symptoms of hypoestrogenism.
HRT employs continuous administration of effective amounts of an estrogen for prolonged periods of time. The administration of estrogens has been associated, however, with endometrial proliferation in women and it is now widely accepted that “unopposed” estrogen therapy substantially increases the risk of endometrial cancer (Cushing et al., 1998. Obstet. Gynecol.91, 35-39; Tavani et al., 1999. Drugs Aging, 14, 347-357). There is also evidence of a significant increase in breast cancer with long-term (10-15 years) use of estrogen therapy (Tavani et al., 1999. Drugs Aging, 14, 347-357; Pike et al., 2000. Steroids, 65, 659-664).
In order to counteract the negative effects of unopposed estrogen therapy, adjunctive progestogen treatment is nowadays commonly applied. Regular progestogen administration is believed to inhibit the continual estrogen stimulation of the endometrium through an anti-proliferative effect and appears to reduce the incidence of endometrial carcinoma in post-menopausal women receiving estrogen replacement therapy (Beral et al., 1999. J. Epidemiol. Biostat., 4, 191-210). Such an adjunctive treatment, generally using synthetic progestogens, is given either in continuous combined regimens with estrogen, or added sequentially, typically for about 14 days each month, to continuous estrogen treatment. Sequential regimens are associated with undesirable vaginal bleeding in response to periodic progestogen withdrawal, while continuous combined therapy frequently results in unpredictable breakthrough bleeding. Unacceptable bleeding of this type is the most frequent reason for discontinuation of hormone replacement therapy.
Additional adverse effects of adjunctive progestogens include oedema, abdominal cramps, breast tenderness and mood symptoms (Hahn, 1989. Am. J. Obstet. Gynecol., 161, 1854-1858). Some synthetic progestogens unfavourably affect lipid patterns and thus negate or attenuate the estrogen induced cardioprotective effects (Sitruk-Ware, 2000. Steroids, 65, 651-658).
To avoid the need for adjunctive progestogens, efforts have been made to synthesise molecules with selective estrogenic properties so as to obtain desirable effects in certain target tissues, such as bone, liver, brain and in tissues that mediate cardioprotection, while minimally affecting other tissues, such as endometrium and breast. These efforts were based on the emerging knowledge that the interaction of estrogens with protein regulating estrogen responsiveness, i.e. estrogen receptors, may vary in different target tissues. Estrogenic, compounds, which selectively modulate estrogen receptors in different target tissues and therefore may be expected to have selective estrogen agonistic/antagonistic effects, are known as selective estrogen receptor modulators (SERMs) (Katzenellenbogen et al., 2000. J. Steroid Biochem. Mol. Biol., 74, 279-285; Burger, 2000. Horm. Res., suppl 3, 25-29).
The optimal SERM is expected to affect differentiated cellular functions without inducing proliferation, because enhanced proliferation is associated with increased cancer risk. Regarding the endometrium, exaggerated proliferation (hyperplasia) has been demonstrated to be a precursor of endometrial cancer. Furthermore, the optimal SERM would eliminate the need for adjunctive progestogen treatment and its adverse effects. An example of a synthetic SERM that is commercially available is raloxifene, a benzothiophene anti-estrogen (Clemett et al., 2000. Drugs, 60, 379-411). A drawback of the known synthetic SERM's is that these molecules do not occur naturally in the human body and that they bear little resemblance to the estrogen receptor agonists that are found in the human body, e.g. estrogens such as estrone, estradiol and estriol.
It is an objective of the present invention to provide a method of hormone replacement therapy, wherein an estrogenic component is administered which does not display the deficits that have been observed for commonly known biogenic or synthetic estrogens and which estrogenic component exhibits SERM-like properties, so that co-administration of progestogen can be avoided. In addition the present method aims to employ an estogenic component that is biogenic or that closely resembles a biogenic estrogenic substance.